Determining the role of the primate raphe-habenula circuit in multi-attribute decision-making

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Value-based decision-making, driven by each individual’s own appraisal of available offers, is an indispensable part of our lives and a key determinant of mental health. Internalizing disorders (e.g. depression, anxiety), commonly feature maladaptive decision-making characterized by the assignment of erroneously low value to rewarding activities and objects. Elucidating the neural basis of value-based decision-making is thus crucial for understanding adaptive behavior and may provide translational insights. The lateral habenula (LHb) is thought to act as the brain’s “bad news” center by broadcasting signals that decrease the value of rewards and is implicated in depressive and anxiety-like behaviors. Moreover, LHb is known to receive strong inputs from the raphe nuclei, the brain’s source of serotonin, a neuromodulator that is the target of most pharmaceuticals for internalizing disorders and many other psychopathologies. The dorsal raphe (DR), the largest serotonergic nucleus, is known to be involved in value-related processes, though the role of its inputs to LHb is unclear. In particular, despite its potential importance, little is known about how the primate raphe-LHb circuit mediates the complex strategies we use every day to choose activities and objects, a decision-making process which requires integration across many reward attributes, such as amount, risk, and delay. We hypothesize that LHb plays a central role in integrating attributes in order to compute the value of offers and guide decisions online, using delay-related signals from DR to discount value. Aim 1 investigates the role of LHb in multi-attribute decision-making. LHb signals are proposed to reflect preference integrated across the many attributes that may define a reward and are ultimately broadcast to cortex and the basal ganglia, regions with a prominent role in selecting actions. Preliminary data suggest that neurons in LHb integrate reward attributes in a manner consistent with negative subjective value and that increasing LHb firing with weak electrical stimulation during an offer’s presentation biases choice away from that offer in a manner consistent with decreased offer value. Aim 2 investigates the role of DR multi-attribute decision-making. DR is proposed to signal variables related to time delays until reward. If this is true in the context of decision-making, DR could send delay and related attributes to LHb to guide decisions. Disruptions in this circuit could then interfere with evaluation and choice of multi-attribute offers, and amelioration of such disruptions by antidepressants could contribute to their therapeutic effects. Subsequent experiments will test the hypothesis that the sensitivity of LHb and choice preference to reward delay is controlled by DR. These Aims will clarify the role of the primate raphe-LHb circuit in multi-attribute decision-making, laying the groundwork for my future investigations of the behavioral and neural systems that underlie internalizing and related disorders and undoubtedly opening the door to new therapeutic avenues. Through these Aims, I will acquire the skills needed to successfully drive this research as I develop into an independent psychiatrist-neuroscientist.